This invention relates generally to nitrogen containing heteroaromatics, with ortho-substituted P1 groups, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula: 
wherein R1 represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.
In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula: 
wherein the heterocycle may be aromatic and groups Axe2x80x94Bxe2x80x94Cxe2x80x94 and Fxe2x80x94Exe2x80x94Dxe2x80x94 are attached to the ring system. Axe2x80x94Bxe2x80x94Cxe2x80x94 can be a wide variety of substituents including a basic group attached to an aromatic ring. The Fxe2x80x94Exe2x80x94Dxe2x80x94 group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT1 agonists which are indole substituted five-membered heteroaromatic compounds of the formula: 
wherein R1 may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Baker et al, in WO 94/02477, discuss 5-HT1 agonists which are imidazoles, triazoles, or tetrazoles of the formula: 
wherein R1 represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Illig et al, in WO 97/47299, illustrate amidino and guanidino heterocycle protease inhibitors of the formula:
R1xe2x80x94Zxe2x80x94Xxe2x80x94Yxe2x80x94W
wherein R1 can be a substituted aryl group, Z is a two carbon linker containing at least one heteroatome, X is a heterocycle, Y is an optional linker and W is an amidino or guanidino containing group. Compounds of this sort are not considered part of the present invention.
Jackson et al, in WO 97/32583, describe cytokine inhibitors useful for inhibiting angiogenesis. These inhibitors include imidazoles of the formula: 
wherein R1 is a variety of heteroaryl groups, R4 is phenyl, naphthyl, or a heteroaryl group, and R2 can be a wide variety of groups. Jackson et al do not teach inhibition of factor Xa. Furthermore, the imidazoles of Jackson et al are not considered part of the present invention.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, D, E, G, J, M, R1a, R1b, and s are defined below, are effective factor Xa inhibitors.
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula I: 
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring M contains, in addition to J, 0-3 N atoms, provided that if M contains 2 N atoms then R1b is not present and if M contains 3 N atoms then R1a and R1b are not present;
J is N or NH;
D is selected from CN, C(xe2x95x90NR8)NR7R9, NHC(xe2x95x90NR8)NR7R9, NR8CH (xe2x95x90NR7), C(O)NR7R8, and (CR8R9)tNR7R8, provided that D is substituted ortho to G on E;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1-2 R;
R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
G is absent or is selected from NHCH2, OCH2, and SCH2, provided that when s is 0, then G is attached to a carbon atom on ring M;
Z is selected from a C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)r, C(O)O(CH2)r, (CH2)rOC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rNR3C(O)(CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(O)NR3(CH2)r, (CH2)rNR3C(O)O(CH2)r, (CH2)rNR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)rNR3SO2(CH2)r, and (CH2)rNR3SO2NR3(CH2)r, provided that Z does not form a Nxe2x80x94N, Nxe2x80x94O, Nxe2x80x94S, NCH2N, NCH2O, or NCH2S bond with ring M or group A;
R1a and R1b are independently absent or selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, xe2x80x94CHxe2x95x90CHxe2x80x94R1xe2x80x2, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, NH(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, R1a and R1b , when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O) R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, CH(xe2x95x90NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1xe2x80x3 is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
B is selected from:
Xxe2x80x94Y NR2R2a, C(xe2x95x90NR2)NR2R2a, NR2C(xe2x95x90NR2)NR2R2a,
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
X is selected from C1-4 alkylene, xe2x80x94CR2(CR2R2b)(CH2)txe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR1)xe2x80x94, xe2x80x94CR2(NR1xe2x80x2R2)xe2x80x94, xe2x80x94CR2(OR2)xe2x80x94, xe2x80x94CR2(SR2)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR2R2axe2x80x94, xe2x80x94CR2R2aS (O)pxe2x80x94, xe2x80x94S(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2xe2x80x94, xe2x80x94NR2S (O)2CR2R2axe2x80x94, xe2x80x94CR2R2aS(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2NR2xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)Oxe2x80x94, xe2x80x94OC(O)NR2xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is selected from:
(CH2)rNR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N, Oxe2x80x94N, or Sxe2x80x94N bond,
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2C, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, CH(xe2x95x90NS(O)2R5)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, C(O)NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, N(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2,
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, Cl, Br, F, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, C(O)NHSO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(xe2x95x90NR3)NR3R3a, NR3C(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)pxe2x80x94C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a,(CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n, at each occurrence, is selected from 0, 1, 2, and 3;
m, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, and 2; and,
t, at each occurrence, is selected from 0, 1, 2, and 3;
provided that Dxe2x80x94Exe2x80x94Gxe2x80x94(CH2)sxe2x80x94 and xe2x80x94Zxe2x80x94Axe2x80x94B are not both benzamidines.
[2] In a preferred embodiment, the present invention provides novel compounds of formulae Ia-Ih: 
wherein, groups Dxe2x80x94Exe2x80x94 and xe2x80x94Zxe2x80x94Axe2x80x94B are attached to adjacent atoms on the ring;
R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
Z is selected from a CH2O, OCH2, CH2NH, NHCH2, C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a Nxe2x80x94N, Nxe2x80x94O, NCH2N, or NCH2O bond with ring M or group A;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
B is selected from: Y, Xxe2x80x94Y, NR2R2a, C(xe2x95x90NR2)NR2R2a, and NR2C(xe2x95x90NR2) NR2R2a;
X is selected from C1-4 alkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR)xe2x80x94, xe2x80x94CR2(NR2R2a)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is NR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N or Oxe2x80x94N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
alternatively, Y is selected from the following bicyclic heteroaryl ring systems: 
K is selected from O, S, NH, and N.
[3] In a more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf: 
wherein;
Z is selected from a C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, C(O)N(CH3) , CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a Nxe2x80x94N or NCH2N bond with ring M or group A.
[4] In an even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
E is phenyl substituted with R or 2-pyridyl substituted with R;
D is selected from NH2, NHCH3, CH2NH2, CH2NHCH3, CH(CH3)NH2, and C(CH3)2NH2, provided that D is substituted ortho to ring M on E; and,
R is selected from H, OCH3, Cl, and F.
[5] In a further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
Dxe2x80x94E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl.
[6] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
Z is C(O)CH2 and CONH, provided that Z does not form a Nxe2x80x94N bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,
B is selected from Xxe2x80x94Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;
R4a is selected from C1-4 alkyl, CF3, S(O)pR5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
X is CH2 or C(O); and,
Y is selected from pyrrolidino and morpholino.
[7] In another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,
B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1xe2x80x2-CF3-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
[8] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
E is phenyl substituted with R or 2-pyridyl substituted with R;
D is selected from NH2, NHCH3, CH2NH2, CH2NHCH3, CH(CH3)NH2, and C(CH3)2NH2, provided that D is substituted ortho to ring M on E; and,
R is selected from H, OCH3, Cl, and F;
Z is C(O)CH2 and CONH, provided that Z does not form a Nxe2x80x94N bond with group A;
A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,
B is selected from Xxe2x80x94Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;
R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;
R4a is selected from C1-4 alkyl, CF3, S(O)pR5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
X is CH2 or C(O); and,
Y is selected from pyrrolidino and morpholino.
[9] In another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
Dxe2x80x94E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl;
A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,
B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1xe2x80x2-CF3-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
[10] In a still further preferred embodiment, the present invention provides a novel compound of formula IIa.
[11] In another still further preferred embodiment, the present invention provides a novel compound of formula IIb.
[12] In another still further preferred embodiment, the present invention provides a novel compound of formula IIc.
[13] In another still further preferred embodiment, the present invention provides a novel compound of formula IId.
[14] In another still further preferred embodiment, the present invention provides a novel compound of formula IIe.
[15] In another still further preferred embodiment, the present invention provides a novel compound of formula IIf.
[16] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
D is selected from xe2x80x94CN, C(xe2x95x90NR8)NR7R9, C(O)NR7R8, NR7R8, and CH2NR7R8, provided that D is substituted ortho to ring M on E;
E is phenyl substituted with R or pyridyl substituted with R;
R is selected from H, Cl, F, OR3, CH3, CH2CH3, OCF3, CF3, NR7R8, and CH2NR7R8;
Z is selected from C(O), CH2C(O), C(O)CH2, NHC(O), and C(O)NH, provided that Z does not form a Nxe2x80x94N bond with ring M or group A;
R1a and R1b are independently absent or selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, NCH2R1xe2x80x3, OCH2R1xe2x88x92, SCH2R1xe2x80x3, N(CH2)2(CH2)tRxe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2, or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
R1xe2x80x2, at each occurrence, is selected from H, C1-3 alkyl, halo, (CF2)rCF3, OR2, NR2R2a, C(O)R2c, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, NR2C(O)R2b, NR2C(O)2R2b, C(O)NR2R2a, SO2NR2R2a, and NR2SO2R2b;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;
B is selected from: Y, Xxe2x80x94Y, NR2R2a, C(xe2x95x90NR2)NR2R2a, and NR2C(xe2x95x90NR2)NR2R2a;
X is selected from CH2, xe2x80x94CR2(CR2R2b) (CH2)txe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR)xe2x80x94, xe2x80x94CH(NR2R2a)xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, and O;
Y is NR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N or Oxe2x80x94N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;
R4, at each occurrence, is selected from xe2x95x90O, OH, Cl, F, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, C(O)NR2R2a, CH(xe2x95x90NH)NH2, NHC (+NH) NH2, SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
R4a, at each occurrence, is selected from xe2x95x90O, OH, Cl, F, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, C(O)NR2R2a, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, xe2x95x90O, OH, OR2, Cl, F, CH3, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, CH(xe2x95x90NH) NH2, NHC (xe2x95x90NH) NH2, and SO2NR2R2a;
R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, benzyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and benzyl; and
alternatively, R7 and R8 combine to form a morpholino group; and,
R9, at each occurrence, is selected from H, C1-6 alkyl and benzyl.
[17] In a another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
E is phenyl substituted with R or 2-pyridyl substituted with R;
R is s elected from H, Cl, F, OCH3, CH3, OCF3, CF3, NH2, and CH2NH2;
Z is selected from a C(O)CH2 and C(O)NH, provided that Z does not form a Nxe2x80x94N bond with group A;
R1a is selected from H, CH3, CH2CH3, Cl, F, CF3, OCH3, NR2R2a, S(O)pR2b, CH2S(O)pR2b, CH2NR2S(O)pR2b, C(O)R2c, CH2C(O)R2c, C(O)NR2R2a, and SO2NR2R2a;
R1b is selected from H, CH3, CH2CH3, Cl, F, CF3, OCH3, NR2R2a, S(O)pR2b, CH2S(O)pR2b, CH2NR2S(O)pR2b, C(O)R2c, CH2C(O)R2c, C(O)NR2R2a, and SO2NR2R2a;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;
phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;
B is selected from: Y and Xxe2x80x94Y ;
X is selected from CH2, xe2x80x94CR2(CR2R2b)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR)xe2x80x94, xe2x80x94CH(NR2R2a)xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, and O;
Y is NR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N or Oxe2x80x94N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;
R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2b, at each occurrence, is selected from CF3, OCH3, CH3, benzyl, and phenyl;
R2c, at each occurrence, is selected from CF3, OH, OCH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2acombine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, CH3, CH2CH3, and phenyl;
R3a, at each occurrence, is selected from H, CH3, CH2CH3, and phenyl;
R4, at each occurrence, is selected from OH, Cl, F, CH3, CH2CH3, NR2R2a, Ch2NR2R2a, C(O)R2b, NR2C(O)NR2b, C(O)NR2R2a, and CF3;
R4a, at each occurrence, is selected from OH, Cl, F, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, CF3, and 1-CF3-tetrazol-2-yl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 1 R6;
R6, at each occurrence, is selected from H, OH, OCH3, Cl, F, CH3, CN, NO2, NR2R2a, CH2NR2R2a, and SO2NR2R2a;
R7, at each occurrence, is selected from H and C1-3 alkyl;
R8, at each occurrence, is selected from H, CH3, and benzyl;
R9, at each occurrence, is selected from H, CH3, and benzyl; and,
t, at each occurrence, is selected from 0 and 1.
[18] In a another still further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;
D is selected from NR7R8, and CH2NR7R8, provided that D is substituted ortho to ring M on E;
R1a is absent or is selected from H, CH3, CH2CH3, Cl, F, CF3, OCH3, NR2R2a, S(O)pR2b, C(O)NR2R2a, CH2S(O)pR2b, CH2NR2S(O)pR2b, C(O)R2c, CH2C(O)R2c, and SO2NR2R2a;
R1b is absent or is selected from H, CH3, CH2CH3, Cl, F, CF3, OCH3, NR2R2a, S(O)pR2b, C(O)NR2R2a, CH2S(O)pR2b, CH2NR2S(O)pR2b, C(O)R2b, CH2C(O)R2b, and SO2NR2R2a;
A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4; phenyl, pyridyl, and pyrimidyl;
B is selected from: Y and Xxe2x80x94Y ;
X is selected from xe2x80x94C(O)xe2x80x94 and O;
Y is NR2R2a, provided that Xxe2x80x94Y do not form a Oxe2x80x94N bond;
alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;
R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;
R2b, at each occurrence, is selected from CF3, OCH3, CH3, benzyl, and phenyl;
R2c, at each occurrence, is selected from CF3, OH, OCH3, CH3, benzyl, and phenyl;
alternatively, R2 and R2a combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;
R4, at each occurrence, is selected from Cl, F, CH3, NR2R2a, and CF3;
R4a, at each occurrence, is selected from Cl, F, CH3, SO2NR2R2a, S(O)pR5, and CF3;
R5, at each occurrence, is selected from CF3 and CH3;
R7, at each occurrence, is selected from H, CH3, and CH2CH3; and,
R8, at each occurrence, is selected from H and CH3.
[19] Specifically preferred compounds of the present invention are selected from the group:
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1- pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl) carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl)phenyl) carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl) phenyl) carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl)phenyl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl)phenyl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;
b 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl) phenyl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide; 3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide; and,
3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;
and pharmaceutically acceptable salts thereof.
[20] More specifically preferred compounds of the present invention are selected from the group:
3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
5-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-3-(N-(2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-N,N-dimethylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-N-methylsulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-sulfamido-[1,1]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-pyrrolidinocarbonyl)phenyl)carboxyamide;
N-Benzylsulfonyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2xe2x80x2-sulfonamido)phenyl)pyrid-2-yl)carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(pyrid-2-yl))pyrid-2-yl)carboxyamide;
N-Benzyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine;
N-Phenylsulfonyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine;
3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-(1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-sulfamido-[1,1]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-5-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-5-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-5-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4,5-difluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4,5-difluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-3-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-3-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-sulfamido-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(2-sulfamido-(1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(N-((Nxe2x80x2-methylsulfonyl)iminoly)pyrrolidino))phenyl)carboxyamide;
3-Trifluoromethyl-1-(2-(N-glycyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-(N-phenylacetyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-(Trifluoromethyl)-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-(N-(glycyl)aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-((N-(N-methylglycyl)aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-carboxamidophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(2-cyanophenyl)-1H-pyrazole-5-(N-(3-fluoro-2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
1-(2xe2x80x2-Aminomethylphenyl)-5-[[(2xe2x80x2-methylsulfonyl)-3-fluoro-[1,1]-biphen-4-yl]aminocarbonyl]-tetrazole;
1-(2xe2x80x2-Aminomethylphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]-tetrazole;
1-[2-(Aminomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-[2-(Aminomethyl)phenyl]-3-methylsulfonyl-5-[(2-fluoro)-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]triazole;
1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-[2-(Aminomethyl)phenyl]-3-trifluoromethyl-5-[((2-fluoro)-(2xe2x80x2-pyrrolidinomethyl)-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole; and,
1-[2-(Aminomethyl)phenyl]-3-trifluoromethyl-5-[((2-fluoro)-(2xe2x80x2-hydroxymethyl)-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
and pharmaceutically acceptable salts thereof.
In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(xe2x95x90NR7)NH2 or its tautomer C(xe2x95x90NH)NHR7 and R7 is selected from OH, C1-4 alkoxy, C6-10 aryloxy, C1-4 alkoxycarbonyl, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, and C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl. More preferred prodrugs are where R7 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups resent in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
The compounds of Formula I in which ring M is pyrrole can be prepared by the procedures described in Schemes 1-9. In Scheme 1 is shown how to prepare pyrroles in which the group Qxe2x80x94E is attached to the pyrrole nitrogen, wherein Q is a functionality that can be converted into D of Formula I, Re is functionality that can be converted into Zxe2x80x94Axe2x80x94B of Formula I and Rf is or can be converted into R1a of Formula I. Oxidation of a furan with bromine in acetic acid can afford a 2,5-diacetoxydihydrofuran which can react with amine Qxe2x80x94Exe2x80x94NH2 to afford a pyrrole. Vilsmeier-Haack formylation with phosphorous oxychloride and DMF preferentially can acylate the pyrrole ring at C-2. Oxidation of the resulting aldehyde can give a carboxylic acid. The carboxylic acid can then be converted into amine derivatives using either the Hofmann degradation of the derived primary amide (Huisgen et. al. Chem. Ber. 1960, 93, 65) or the Curtius rearrangement of the derived acyl azide (J. Prakt. Chem. 1909, 42, 477). Derivatives which contain a sulfur atom attached to the pyrrole ring can be obtained by direct sulfonation with pyridine sulfur trioxide complex to give the sulfonic acids or treatment with copper (II) thiocyanate (J. Het. Chem. 1988, 25, 431) followed by the reduction of the intermediate thiocyanate with sodium borohydride to give a mercaptan. 
In Scheme 2 is shown how to prepare pyrroles in which Qxe2x80x94E is attached to the 2-position, wherein Rf and Rg collectively are hydrogen or a group that can be converted into R1a and R1b of Formula I. The Hantzsch pyrrole synthesis is a versatile reaction involving the cyclization of an appropriate xcex2-ketoester with an xcex1-halo ketone or aldehyde in the presence of a primary amine (Ber. Dtsch. Chem. Ges. 1890, 23, 1474). The xcex2-ketoesters can be prepared from acid chlorides (X=Cl) by the addition of the magnesium anion of potassium alkylmalonate followed by decarboxylation (Synthesis 1993, 290). Alternatively, xcex2-ketoesters can be prepared from an appropriate aldehyde (R=H) by Reformatsky reaction with an xcex1-bromoacetate followed by oxidation. Cyclization with an xcex1-halo ketone or aldehyde in the presence of a primary amine can afford pyrroles. Acidic hydrolysis of the 3-carboalkoxy pyrrole can afford the carboxylic acids. Pyrroles which contain a 3-amino substituent can be prepared from the acids by treatment with phosphoryl azide and triethylamine to effect a Curtius rearrangement to afford the isocyanates (J. Med. Chem. 1981, 24, 33) which upon hydrolysis can yield 3-aminopyrroles. Pyrroles which contain a sulfur atom at C-3 can be prepared from the acids by employing the Hunsdiecker procedure to give the 3-bromo derivatives. Halogen-metal exchange at low temperature with an alkyllithium reagent can afford the 3-lithio derivative which can be quenched with a variety of electrophiles, such as S8 to afford thiols directly or Cu(SCN)2 to afford a thiocyanate which can be reduced with sodium borohydride. The thiols can further be oxidized to the sulfonic acid derivatives by an oxidant such as KMnO4. 
In Scheme 3 is shown how to prepare pyrroles in which Qxe2x80x94E is attached to the 3-position. This scheme relies upon the extremely versatile Knorr pyrrole synthesis, which involves condensation of a-aminoketones with xcex2-ketoesters. The xcex1-aminoketones can be prepared from xcex2-ketoesters (Scheme 2) by nitrosation followed by reduction with zinc/acetic acid. Condensation of xcex1-aminoketones with appropriate xcex2-ketoesters can afford good yields of pyrroles. These intermediates are very versatile and can be converted into pyrroles with a wide variety of substituents with varying substitution patterns. For cases wherein Re (Zxe2x80x94Axe2x80x94B precursor) is at the 2-position, acidic hydrolysis can selectively hydrolyze the C-3 ester. Heating should then effect decarboxylation. Hydrolysis of the 2-carboxylic acid can be achieved under basic conditions. Curtius rearrangement of the acid as described previously can afford the amino derivatives. To prepare compounds with a sulfur atom attached to C-2, basic hydrolysis and decarboxylation can afford the C-2 unsubstituted pyrroles. These pyrroles can undergo electrophilic substitution to afford thiols (Cu(SCN)2, then NaBH4) and sulfonic acids (pyridine SO3 complex or chlorosulfonic acid). The R1a group contained in Formula I can be derived either from the remaining ester or from Rf. Alternatively, the thiol and sulfonic acid derivatives can also be derived form the C-2 acids by manipulation of the carboxylic acid group as described previously. 
In Scheme 4 is shown how to prepare pyrroles in which Qxe2x80x94E is attached to the 3-position. Cyclization of xcex1-aminoketones as described previously with xcex2-ketoesters can afford pyrroles. Hydrolysis under basic conditions can selectively hydrolyze the C-2 ester which upon heating should undergo decarboxylation to afford 2-unsubstituted pyrroles. The C-3 ester can then be hydrolyzed under acidic conditions to afford the 3-carboxypyrroles. Curtius rearrangement under conditions described previously can afford the 3-aminopyrroles. The carboxylic acids can be used to prepare the 3-mercapto and 3-sulfonic acid derivatives. The Hunsdiecker procedure can be used to prepare the 3-bromopyrroles. Halogen metal exchange with t-BuLi at low temperature followed by quenching with copper isocyanate should introduce an isocyanate group at C-3. This intermediate can be reduced with sodium borohydride to afford the 3-mercaptopyrroles. Alternatively, the carboxylic acids can be decarboxylated to afford pyrroles which can be N-protected with a bulky protecting group such as triisopropylsilyl (TIPS). This bulky group directs electrophilic substitution to C-3 of the pyrrole ring. Thus, reaction with copper isocyanate followed by sodium borohydride reduction and then fluoride induced TIPS deprotection can afford 3-mercaptopyrroles. Sulfonation of N-protected pyrrole with pyridine sulfur trioxide complex can again be directed to C-3 of the pyrrole to afford, after TIPS deprotection, the 3-sulfonic acids. 
Another general method of pyrrole synthesis that can be used to prepare compounds of the present invention is shown in Scheme 5. This approach (Cushman et. al. J. Org. Chem. 1996, 61, 4999) uses N-protected a-aminoketones and N-protected xcex1-aminoaldehydes which are readily available from xcex1-amino acids by initial preparation of the N-methoxy-N-methylamides followed by addition of an alkyl Grignard reagent (to produce ketones) or by reduction with a hydride reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride. These aldehydes and ketones can be allowed to react with the enolates of additional ketones to afford intermediate aldol addition products which under acidic conditions cyclize to form pyrroles. The reacting partners in this approach can be of wide scope and can be chosen so that one skilled in the art will be able to prepare varied pyrroles. 
Another very general method of pyrrole synthesis useful for preparing compounds of the present invention is the Paal-Knorr reaction shown in Scheme 6. This reaction involves the reacting 1,4-diketones or 1,4-ketoaldehydes with primary amines to afford pyrroles. The starting 1,4-diketones and 1,4-ketoaldehydes can be prepared using standard enolate chemistry or by other procedures which are familiar to those skilled in the art of organic synthesis. The reaction is of wide scope and the starting materials can be chosen so that a variety of pyrroles can be prepared. 
In Scheme 7 is shown how the compounds of Schemes 1-6 wherein Re is a carboxylic ester group can be converted into compounds containing the Zxe2x80x94Axe2x80x94B residue. For the amide linker (Formula I, Z=xe2x80x94CONHxe2x80x94), when Re=carboalkoxy, it can be hydrolyzed to the acid under either basic or acidic conditions depending on the substitution pattern, as described previously. Formation of the acid chloride with thionyl chloride followed by the addition of an appropriate amine H2Nxe2x80x94Axe2x80x94B can afford the amide-linked compounds. Alternatively, the acid can be combined with amine H2Nxe2x80x94Axe2x80x94B in the presence of a suitable peptide coupling agent, such as BOP-Cl, HBTU or DCC. In another method the ester can be directly coupled with an aluminum reagent, prepared by the addition of trimethylaluminum to the amine H2Nxe2x80x94Axe2x80x94B.
To form ether- or thioether-linked compounds of Formula I (Z=xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94) the acid can be reduced to the alcohol. Preferred procedures for this transformation are reduction with borane THF complex, or a procedure involving the reduction of the mixed anhydride with sodium borohydride (IBCF=isobutyl chloroformate and NMM=N-methylmorpholine). Completion of the ether and thioether linked compounds of Formula I can readily be accomplished by the Mitsonobu protocol with an appropriate phenol, thiophenol or hydroxy- or mercaptoheterocycle HXxe2x80x94Axe2x80x94B (X=O,S) (Formula I, A=aryl or heteroaryl). Other ethers or thioethers (X=O,S) can be prepared following initial conversion of the alcohol to a suitable leaving group, such as tosylate. Where X=S, thioethers can be further oxidized to prepare the sulfones (Formula I, Z=xe2x80x94CH2SO2xe2x80x94).
To prepare the amine-linked compounds of Formula I (Z=xe2x80x94CH2NHxe2x80x94) the alcohol can be oxidized to the aldehyde by a number of procedures, two preferred methods of which are the Swern oxidation and oxidation with pyridinium chlorochromate (PCC). Alternatively, the aldehyde may be directly prepared by direct formylation of the pyrrole ring by the Vilsmeier-Haack procedure in certain cases, as described in previous schemes. Reductive amination of the aldehyde with an appropriate amine H2Nxe2x80x94Axe2x80x94B and sodium cyanoborohydride can then afford the amine linked compounds.
The aldehyde also can be used to prepare the ketone-linked compounds of Formula I (Z=xe2x80x94COCH2xe2x80x94). Treatment with an organometallic species can afford the alcohol. The organometallic species (wherein M=magnesium or zinc) can preferably be prepared from the corresponding halide by treatment with metallic magnesium or zinc. These reagents should readily react with aldehydes to afford alcohols. Oxidation of the alcohol by any of a number of procedures, such as the Swern oxidation or PCC oxidation, can afford the ketones-linked compounds. 
Additional compounds of Formula I in which the linking group m/z contains a nitrogen atom attached to ring M can be prepared by the procedures described in Scheme 8. The amines can be converted to sulfonamides (Formula I, m/z-NHSO2xe2x80x94) by treatment with an appropriate sulfonyl chloride Bxe2x80x94Axe2x80x94SO2Cl in 10 the presence of a base such as triethylamine. The amines can be converted into amides (Formula I, Z=xe2x80x94NHCOxe2x80x94) by treatment with an appropriate acid chloride Clxe2x80x94COxe2x80x94Axe2x80x94B in the presence of a base or by treatment with an appropriate carboxylic acid HOxe2x80x94COxe2x80x94Axe2x80x94B in the presence of a suitable peptide coupling agent, such as DCC, HBTU or BOP. The amines can also be converted into amine-linked compounds (Formula I, Z=xe2x80x94NHCH2xe2x80x94) by reductive amination with an appropriate aldehyde OHCxe2x80x94Axe2x80x94B. 
Additional compounds of Formula I in which the linking group Z contains a sulfur atom attached to ring M can be prepared by the procedures described in Scheme 9. Treatment of sulfonic acids with phosphorous pentachloride followed by treatment with an appropriate amine H2Nxe2x80x94Axe2x80x94B can afford sulfonamide-linked compounds (Formula I, Z=xe2x80x94SO2NHxe2x80x94). The thiols can be alkylated with a suitable alkylating reagent in the presence of a base to afford thioethers (Formula I, Z=xe2x80x94SCH2xe2x80x94). These compounds can be further oxidized by a variety of reagents to afford the sulfone-linked compounds (Formula I, Z=xe2x80x94SO2CH2xe2x80x94). 
Compounds of Formula I wherein ring M is an imidazole can be formed using procedures described in Schemes 10-16. N-Substituted imidazole derivatives can be made by the general procedure shown in Scheme 10, wherein Vxe2x80x2 is either V or a precusor of (CH2)nV, V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide, n is 0 and 1, and PG is either a hydrogen or a protecting group. Substitution can be achieved by coupling an imidazole with a halogen containing fragment Qxe2x80x94Exe2x80x94G-Hal in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base, followed by conversion of Vxe2x80x2 to (CH2)nV. Then, Q can be converted to D, and finally V can be converted to xe2x80x94Zxe2x80x94Axe2x80x94B following the procedures outlined in Schemes 7-9. Alternatively, V can be converted to Zxe2x80x94Axe2x80x94B followed by deprotection of N. This product can then be coupled as before to obtain the desired imidazole. 
One way to make amidino-phenyl-imidazole derivatives is shown in Scheme 11. 4-Imidazole carboxylic acid can be treated with thionyl chloride and then coupled with H2Nxe2x80x94Axe2x80x94B in the presence of a base and then be heated with 3-fluorobenzonitrile in the presence of a base. The Pinner reaction using standard procedures known to those of skill in the art can be used to form the amidino group. 
1,2-Disubstituted and 1,5-disubstituted imidazole derivatives can be made by the general procedures described in Scheme 12, wherein R1b is either a hydrogen or an alkyl group and U is aldehyde, ester, acid, amide, amino, thiol, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide. Step a involves coupling in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base. When R1b is a hydrogen, it can be deprotonated with a lithium base and trapped by formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine), or isocyanate to give 1,2-disubstituted imidazoles (Route b1). Also, in Route b1 when R1b is CH3, it can be oxidized with SeO2, MnO2, NaIO4/cat. RhCl3, or NBS to form U. When R1b is hydrogen, sequential deprotonation and quenching with a lithium base and trimethysilyl chloride, followed by a second deprotonation with a lithium base and quenching with formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine), or isocyanate can afford 1,5-disubstituted imidazoles (Route b2). When R1b is not hydrogen, the procedure of Route b2 can again be used to form 1,5-disubstituted imidazoles (Route b3). 
A preferred way of making 1,2-disubstituted and 1,5-disubstituted imidazole derivatives is shown in Scheme 13. Imidazole can be heated with 3-fluorobenzonitrile in the presence of a base. The coupled product can then be treated with an alkyl lithium base and quenched with ClCO2Me to give the 1,2-disubstituted compound. Further treatment with a solution prepared of H2Nxe2x80x94Axe2x80x94B in trimethylaluminum can give the amide, which can be further modified via the Pinner reaction to form the desired compound. The 1,5-disubstituted compounds can be made using the same procedure, except that the initial anion is protected and a second anion is formed which is then quenched as noted above. Further modifications can follow the same procedures as the 1,2-disubstituted compounds. 
Another way of making 1,2-disubstituted imidazole derivatives is described in Scheme 14. By reacting an N-substituted imidazole with a cyanate, the amide can be obtained. This amide can then be coupled with group B as will be described later. 
Another means of making 1,5-disubstituted imidazole derivatives is described in Scheme 15. Alkylation with 2-bromoethylacetate and subsequent reaction with Gold""s reagent in the presence of a base, such as NaOMe, or LDA, can form ester substituted imidazoles which can be further modified as previously discribed. 
A general procedure to make 2,4,5-trisubstituted or 4,5-disubstituted-imidazole derivatives is shown in Scheme 16. After metal halogen exchange of the Qxe2x80x94Exe2x80x94G fragment, it can be reacted with the amide shown, brominated with NBS and cyclized with excess NH3 and R1aCO2H to afford an imidazole. This can then be modified as before. 
A general procedure to make 4,5-disubstituted triazole derivatives is described in Scheme 17. Ethyl propiolate can be substituted in the presence of CuI/Pd and then reacted with NaN3 to form a triazole. The triazole can be converted as described previously. 
The tetrazole compounds of the present invention where Z is xe2x80x94CONHxe2x80x94 can be prepared as exemplified in Scheme 18. An appropiately substituted amine can be acylated with ethyl oxalyl chloride. The resulting amide can be converted to the tetrazole either by the methods described by Duncia (J. Org. Chem. 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768). The amide can be converted to the iminoyl chloride first and the reacted with NaN3 to form the 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorg. and Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carboethoxytetrazole can then be further modified as described in Scheme 7.
The tetrazole compounds of the present invention where Z is xe2x80x94COxe2x80x94 can also be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073) using an appropriately substituted acyl chloride as starting material. The ketone-linker can be reduced to compounds wherein Z is alkyl. 
The methods described in Scheme 18 can also be used to synthesize compounds where the Exe2x80x94Q is linked to the carbon atom of the tetrazole as shown in Scheme 19. The 5-substituted tetrazole can then be alkylated or acylated to give the desired products. 
The tetrazole compounds of the present invention wherein Z is xe2x80x94SO2NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, SO2xe2x80x94 can be prepared from the thiol prepared as shown in Scheme 20. Appropiately substituted thioisocyanate can be reacted with sodium azide to give the 5-thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592). The thio-compound can be modified as described in Scheme 9.
The tetrazole compounds of the present invention wherein Z is xe2x80x94Oxe2x80x94 can be prepared via the same method described in Scheme 20 by using appropiately substituted isocyanate as the starting material. The hydroxy compound can be modified similarity to the thiols described in Scheme 9. 
The tetrazole compounds of the present invention wherein Z is xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94 can be prepared from 5-aminotetrazole, which can be prepared by Smiles Rearrangement as shown in Scheme 21. The thio-compound prepared as described in Scheme 20 can be alkylated with 2-chloroacetamide. The resulting compound can then be refluxed in ethanolic sodium hydroxide to give the corresponding 5-amino-tetrazole (Chem. Pharm. Bull. 1991, 39, 3331-3334). The resulting 5-amino-tetrazole can then be alkylated or acylated to form the desired products. 
Pyrazoles of Formula I (such as those described in Scheme 22) can be prepared by the condensation of an appropriately substituted hydrazine with a variety of diketo esters. Condensations of this type typically afford a mixture of pyrazole regioisomers which can be effectively separated via silica gel column chromatography. The esters can be converted to Zxe2x80x94Axe2x80x94B as previously described.
Alternatively, if in Scheme 22, the starting diketone contains CH3 in place of CO2Et, then the resulting methyl pyrazole can be separated and oxidized as in Route b1 in Scheme 12 to form the pyrazole carboxylic acid. 
When ketoimidates are used for condensations with hydrazines the corresponding pyrazole amino esters are obtained (Scheme 23). Conversion of these intermediates to the final compounds of formula I can then be accomplished by the protection of the amino functionality with a suitable protecting group or by derivatization (e.g. sulfonamide) and then modifying the ester as previously noted. 
As shown in Scheme 24, pyrazoles wherein the 4-position is substituted can be prepared by bromination (bromine or NBS in either dichloromethane or acetic acid) of the initial pyrazole. Conversion of 4-bromo-pyrazole to 4-carboxylic acid pyrazole can be accomplished by a number of methods commonly known to those in the art of organic synthesis. Further manipulations as previously described can afford pyrazoles of the present invention. 
Pyrazoles can also be prepared according to method described in Scheme 25. The bromo-pyrazoles are formed as in Scheme 24. QE can then be coupled using palladium catalepsy Suzuki cross-coupling methodology. Further modification is achieved as previously described. 
5-substituted phenylpyrazoles can be prepared by the method shown in Scheme 26. Conversion of the 5-hydroxy pyrazole to its triflate (triflic anhydride, lutidine in dichloromethane) or bromide (POBr3) followed by palladium Suzuki cross-coupling with an apppropriately substituted phenylboronic acid should then afford 5-substituted pyrazoles. Conversion of this intermediate to the 4-bromo derivative followed by its carbonylation as described in Scheme 24 should then afford the appropriate ester which can be further afford the compounds of formula I. 
1-Substituted-1,2,3-triazoles of the present invention can be prepared by the treatment of an appropriately substituted azide with a variety of dipolarophiles (Tetrahedron 1971, 27, 845 and J. Amer. Chem. Soc. 1951, 73, 1207) as shown in Scheme 27. Typically a mixture of regioisomers are obtained which can be easily separated and elaborated to the triazole carboxylic acids. Further transformations as previously described can then afford the compounds of the present invention. 
1,2,4-Triazoles of the present invention can be obtained by the methodology of Huisgen et al (Liebigs Ann. Chem. 1962, 653, 105) by the cycloaddition of nitriliminium species (derived from the treatment of triethylamine and chloro hydrazone) and an appropriate nitrile dipolarophile (Scheme 28). This methodology provides a wide variety of 1,2,4 triazoles with a varied substitution pattern at the 1, 3, and 5 positions. 
1,2,4 Triazoles can also be prepared by the methodology of Zecchi et al (Synthesis 1986, 9, 772) by an aza Wittig condensation (Scheme 29). 
1,2,4-Triazoles wherein the xe2x80x94Exe2x80x94D(Q) substituent is at the 5-position of the triazole can be obtained as shown in Scheme 30. 
1,3,4-Triazoles of the present invention can be obtained via the methodology of Moderhack et al (J. Prakt. Chem. 1996, 338, 169). As shown in Scheme 31, this reaction involves the condensation of a carbazide with an appropriately substituted commercially available thioisocyanate to form the cyclic thiourea derivative. Alkylation or nucleophilic displacement reactions on the thiono-urea intermediate can then afford a thio-alkyl or aryl intermediate which can be hydrolysed, oxidized and decarboxylated to the 5-H 2-thio-triazole intermediate which can be converted to the compounds of the present invention. Alternatively the thiono-urea intermediate can be oxidized directly to the 2-H triazole which can then be converted to the ester and modified as previously described. The thiono-urea intermediate can also be oxidized to the sulfonyl chloride by methods shown previously. 
The imidazole core shown in Scheme 32 can be prepared by the condensation of 3-cyanoaniline with n-butylglyoxylate to afford the imine which can then be treated with TosylMIC in basic methanol to afford the desired imidazole compound. Coupling of the ester under standard conitions then affords a variety of analogs which then can be further manipulated to afford e.g. the benzylamine or the benzamidines. 
Compounds of the present invention wherein AB is a biphenylamine or similar amine may be prepared as shown in Scheme 33. 4-Bromoaniline can be protected as Boc-derivative and coupled to a phenylboronic acid under Suzuki conditions (Bioorg. Med. Chem. Lett. 1994, 189). Deprotection with TFA provides the aminobiphenyl compound. Other similar amines wherein A and/or B are heterocycles can be prepared by the same method using appropiately substituted boronic acids and arylbromide. The bromoaniline can also be linked to the core ring structures first as described above, and then undergo a Suzuki reaction to give the desired product. 
Compounds of the present invention wherein Axe2x80x94B is Axe2x80x94Xxe2x80x94Y can be prepared like the piperazine derivative shown in Scheme 34. 
Scheme 35 shows how one can couple cyclic groups wherein X=NH, O, or S. 
When B is defined as Xxe2x80x94Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.
The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from xe2x88x9220xc2x0 C. to the reflux point of the solvent and with or without a trialkylamine base.
The coupling chemistry of Table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0xc2x0 C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temperature (xe2x88x9220xc2x0 C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide.dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)3 according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).
The ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.
The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D. A combination of wet alumina and oxone can provide a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.
In Table E several methods of transforming a functional group Q into group D of Formula 1 are shown. While not all possible functional groups for Q and D are listed and the synthetic methods suggested are not comprehensive, Table E is meant to illustrate strategies and transformations available to a practitioner skilled in the art of organic synthesis for preparing compounds of Formula 1. In reaction 1 of Table E the transformation of a nitrile into an amidine by the Pinner methodology is shown; in reaction 2 the direct reduction of a nitrile by a hydride reducing agent to a methylene amine is illustrated. In reaction 3, the utility of a carboxylic acid, which may be readily derived from its ester or a nitrile if necessary, in the preparation of a methylene amine is shown. This synthetic route is exceptionally flexible because of the several stable intermediates prepared en route to the final product. As outlined, formation of an activated analog, such as the mixed anhydride, allows for the mild reduction of the acid to the methylene alcohol, this may in turn be transformed into a leaving group by sulfonylation or halogenation or protected with a suitable protecting group to be transformed later in the synthesis as the chemistry demands. Once the methylene alcohol is so activated, displacement by an efficient nitrogen nucleophile, such as azide anion, can again provide another suitably stable analog,xe2x80x94the methylene azidexe2x80x94which may be used as a protected form of the methylene amine or transformed directly into the methylene amine group by reduction. Reaction 4 addresses the problem of appending the amine functionality directly through a bond to group E of Formula 1. Once again, the carboxylic acid provides a convenient entre into this selection for group D. The well-know Curtius rearrangement is illustrated here; an activated acid analog can be used to form an acyl azide which upon thermal decomposition is rearranged to the corresponding isocyanate. The isocyanate intermediate may then be captured as a stable carbamate by the addition of a suitable alcohol and further heating. This carbamate can be used as a stable protecting group for the amine or cleaved directly to the desired D. Alternatively, it may be convenient to quench the isocyanate intermediate with water to give the amine directly.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.